911108-90-2Relevant articles and documents
Rational design of carbamate-based dual binding site and central AChE inhibitors by a “biooxidisable” prodrug approach: Synthesis, in vitro evaluation and docking studies
??n?a?, Mihaela-Liliana,Gembus, Vincent,Alix, Florent,Barré, Ana?s,Coadou, Ga?l,Truong, Lina,Sebban, Muriel,Papamica?l, Cyril,Oulyadi, Hassan,Levacher, Vincent
, p. 171 - 182 (2018)
Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent pseudo-irreversible quinolinium salts AChE inhibitors 2 previously reported, a new set of diversely substituted quinolinium salts 2a-p was prepared and assayed for their inhibitory activity against AChE. Structure-activity relationship (SAR) analysis of 2a-p coupled with molecular docking studies allowed us to determine which position of the quinolinium scaffold may be considered to anchor the phtalimide fragment presumed to interact with the peripheral anionic site (PAS). In addition, molecular docking provided insight on the linker length required to connect both quinolinium and phatlimide moieties without disrupting the crucial role of quinolinium salt moiety within the catalytic active site (CAS); namely placing the carbamate in the correct position to trigger carbamylation of the active-site serine hydroxyl. Based on this rational design, the putative dual binding site inhibitor 4 and its prodrug 3 were synthesized and subsequently evaluated in vitro against AChE. Pleasingly, whereas compound 4 showed to be a highly potent inhibitor of AChE (IC50 = 6 nM) and binds to AChE-PAS to the same extent as donepezil, its prodrug 3 revealed to be inactive (IC50 > 10 μM). These preliminary results constitute one of the few examples of carbamate-based dual binding site AChE inhibitors.
Rational design of central selective acetylcholinesterase inhibitors by means of a "bio-oxidisable prodrug" strategy
Bohn, Pierre,Le Fur, Nicolas,Hagues, Guillaume,Costentin, Jean,Torquet, Nicolas,Papamicael, Cyril,Marsais, Francis,Levacher, Vincent
experimental part, p. 2612 - 2618 (2009/10/30)
This work deals with the design of a "bio-oxidisable prodrug" strategy for the development of new central selective acetylcholinesterase inhibitors. This prodrug approach is expected to reduce peripheral anticholinesterase activity responsible for various
NEW HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS, IN PARTICULAR AS ANTI-ALZHEIMER AGENTS
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Page/Page column 86-87, (2008/06/13)
The invention is related to compound which comprises at least one radical C=Y, Y being O or S, and an oxidable and non protonable nitrogen atom N wherein the distance (d) between the at least one carbon atom of the radical group C=Y and the nitrogen atom, when oxidized, is comprised between 0.3 and 0.8 nanometers. The invention is related to new heterocyclic compounds defined by formula G, their preparation, to pharmaceutical compositions comprising them and to their use as therapeutic agents, particularly in the treatment of neurodegenerative or Alzheimer disease.
